Core G: Imaging Summary The imaging data set collected in the Dominantly Inherited Alzheimer Network (DIAN) participants to date represents a highly valuable resource for Alzheimer's disease (AD) research. It has supported cross sectional analysis of PET and MRI data to develop a timeline for imaging biomarkers in autosomal dominant AD (ADAD). With this renewal application, the DIAN Imaging Core will continue to obtain and analyze longitudinal imaging data that is fully integrated with clinical, psychometric and cerebrospinal fluid (CSF) biomarkers, and will allow for mutation-specific genotype-phenotype analysis. Imaging Core will be responsible for the acquisition, quality control, and analysis of the MRI and PET neuroimaging for DIAN. Carriers of AD-causing mutations and their non-carrier siblings are enrolled and followed in the Clinical Core through the international DIAN performance sites. Participants will undergo structural and functional MRI, amyloid PET, tau PET, and metabolic PET imaging every 2 years, in conjunction with their clinical visits. The source imaging data and post-processed data will be available to collaborating and outside investigators and will be distributed by the Informatics and Biostatistics cores. For tau PET, we will now obtain scans with the tracers [18F]-MK-6240, [18F]-AV-1451 (aka Flortaucipir, T807), and [18F]-PI-2620. Because no single tracer has the international distribution to reach all sites, each site is assigned one for the three tau PET tracers. Using multiple tracers maximizes the number of DIAN sites that can perform tau PET imaging. Including multiple tracers across the study diminishes the risk of choosing one tracer for such a large, international study of unique participants. Approximately 1/3 of participants will undergo imaging with each tracer. We recognize the limitations of using multiple tracers in the same study and have taken steps to minimize this risk. Based upon our preliminary work, each tracer is independently powered to detect significant effects (see Project 2, Approach). Further, our current proposal is adaptive. If our immunohistochemistry and autoradiographic work (Project 2) demonstrates that one candidate tracer is unsuitable (i.e. THK-5351 binding to monoamine oxidase B44), it will be replaced with another. Over the course of the proposal we will also work with Pharma partners to strengthen tracer availability to a wider international network.